CA2693088C - Antimicrobial compounds, their synthesis and their use for treatment of mammalian infections - Google Patents
Antimicrobial compounds, their synthesis and their use for treatment of mammalian infections Download PDFInfo
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- CA2693088C CA2693088C CA2693088A CA2693088A CA2693088C CA 2693088 C CA2693088 C CA 2693088C CA 2693088 A CA2693088 A CA 2693088A CA 2693088 A CA2693088 A CA 2693088A CA 2693088 C CA2693088 C CA 2693088C
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- benzothiazin
- nitro
- trifluoromethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
Abstract
The present invention relates to new antimicrobial compounds, their synthesis and their use for treatment of mammalian infections. The present invention aims at the generation of new compounds with activity against mycobacteria as potential new tuberculosis drugs to overcome problems concerning resistance and drug intolerance. This aim has been solved by providing compounds of the formula 1 wherein R1 and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONR10R11, CHO, F, Cl, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl; R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1 -3 chain members, F, Cl, Br, lower alkoxy; R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-7 chain members; R is a radical: wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals wherein n is 1-4: R7 - R13 are, independently of each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -5 chain members, phenyl, benzyl or R7 and R8 together R10 and R11 together, R12 and R13 together represent a linear or branched aliphatic bivalent radical having 1 -7 chain members; R14 and R15 are, independently of each other, H, linear or branched aliphatic radical having 1 -5 chain members, F, Cl, Br, NO2, NH1, CF3.
Description
ANTIMICROBIAL COMPOUNDS, THEIR SYNTHESIS AND THEIR USE
FOR TREATMENT OF MAMMALIAN INFECTIONS
Descrintion The present invention relates to novel benzothiazin derivatives and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria.
Thiazinone, their derivatives and their use as antibacterial agents, especially against mycobacteria (TB), laid open for public in AR 24 25 67 Al, AU 37 04 400 Al, CA 13 22 551 Cl or EP 0 245 901 B1 for instance.
As known, there is a threatening worldwide increase in tuberculosis infections with inycobacteria which developed resistance against the available therapeutics (B.R.Bloom, J.L.Murray, Tuberculosis:
commentary on a reemergent killer. Science 1992, 257, 1055-1064).
Extremely dangerous is the development of multidrug resistant (MDR) 70 mrcobacteria. These are mycobacteria, resistant at least against two of the most active tuberculosis drugs, isoniazid and rifampicin, but also against streptomycin, pyranzinamid and ethambutol. The proportion of MDR-TB in some countries is already more than 20%. Even more threatening became the situation since the first cases of XDR-TB
(extremly resistant TB) were diagnosed last year in South Africa. Now XDR-TB is already spread over all continents. Mycobacteria causing XDR-TB are resistant against the first line TB drugs Rifampicin, Isoniazid, Pyrazinamid, Etharnbutol and additionally against the second line chinolones and aminoglycosides. (Nature Med. 2007,13, 295-298) Together with the increased number of TB diseases generally, worldwide it causes about 2.000.000 deaths annually.
For the treatment of such diseases, like (TB) or leprosy, there is an urgent need for new drugs with new mechanisms of actions, especially to overcome drug resistance and to overcome the known dramatic side effects of the available drugs.
. .. .
FOR TREATMENT OF MAMMALIAN INFECTIONS
Descrintion The present invention relates to novel benzothiazin derivatives and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria.
Thiazinone, their derivatives and their use as antibacterial agents, especially against mycobacteria (TB), laid open for public in AR 24 25 67 Al, AU 37 04 400 Al, CA 13 22 551 Cl or EP 0 245 901 B1 for instance.
As known, there is a threatening worldwide increase in tuberculosis infections with inycobacteria which developed resistance against the available therapeutics (B.R.Bloom, J.L.Murray, Tuberculosis:
commentary on a reemergent killer. Science 1992, 257, 1055-1064).
Extremely dangerous is the development of multidrug resistant (MDR) 70 mrcobacteria. These are mycobacteria, resistant at least against two of the most active tuberculosis drugs, isoniazid and rifampicin, but also against streptomycin, pyranzinamid and ethambutol. The proportion of MDR-TB in some countries is already more than 20%. Even more threatening became the situation since the first cases of XDR-TB
(extremly resistant TB) were diagnosed last year in South Africa. Now XDR-TB is already spread over all continents. Mycobacteria causing XDR-TB are resistant against the first line TB drugs Rifampicin, Isoniazid, Pyrazinamid, Etharnbutol and additionally against the second line chinolones and aminoglycosides. (Nature Med. 2007,13, 295-298) Together with the increased number of TB diseases generally, worldwide it causes about 2.000.000 deaths annually.
For the treatment of such diseases, like (TB) or leprosy, there is an urgent need for new drugs with new mechanisms of actions, especially to overcome drug resistance and to overcome the known dramatic side effects of the available drugs.
. .. .
- 2 -Object of the invention The present invention aims at the generation of new compounds with activity against mycobacteria as potential new tuberculosis drugs to overcome problems concerning resistance and drug intolerance.
In accordance with an aspect of the present invention, there is provided a compound of formula I
RI Re I
0Re N
(I) or a salt thereof, wherein R1 and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONRI R11, CHO, F, Cl, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
R6 is a radical:
\
X ¨V1R15 Ri4 wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals:
N-iCli )11 irTh, __tii) or wherein n is 1-4;
. -- 2a -R7-R13 are independently from each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, RI and RII
together, R12 and R13 together represent a linear or branched aliphatic 5 bivalent radical having 1-7 chain members;
RI4 and R15 are independently from each other H, a linear or branched aliphatic radical having 1-5 chain members, F, Cl, Br, NO2, NH2, or CF3.
Solution of the technical problem This aim has been solved by providing compounds of the formula I
R3 S..,.N,,,.
N
(I) wherein RI and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONRI Ru, CHO, F, Cl, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
15 R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
20 R6 is a radical:
\R
wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals wherein n is 1-4:
In accordance with an aspect of the present invention, there is provided a compound of formula I
RI Re I
0Re N
(I) or a salt thereof, wherein R1 and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONRI R11, CHO, F, Cl, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
R6 is a radical:
\
X ¨V1R15 Ri4 wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals:
N-iCli )11 irTh, __tii) or wherein n is 1-4;
. -- 2a -R7-R13 are independently from each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, RI and RII
together, R12 and R13 together represent a linear or branched aliphatic 5 bivalent radical having 1-7 chain members;
RI4 and R15 are independently from each other H, a linear or branched aliphatic radical having 1-5 chain members, F, Cl, Br, NO2, NH2, or CF3.
Solution of the technical problem This aim has been solved by providing compounds of the formula I
R3 S..,.N,,,.
N
(I) wherein RI and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONRI Ru, CHO, F, Cl, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
15 R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
20 R6 is a radical:
\R
wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals wherein n is 1-4:
3 PCT/EP2008/005142 \N¨(CH2)n OR1 or \ /N
4, R15"¨'/
R13 are, independently of each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, Rp3 and K
together, R12 and R13 together represent a linear or branched aliphatic bivalent radical having 1-7 chain members;
R14 and R15 are, independently of each other, H, linear or branched aliphatic radical having 1-5 chain members, F, Cl, Br, NO2, NH2, CF3.
In a preferred embodiment the invention concerns compounds of the formula (I) selected from the group consisting of 2-[4-(2-R14,5-R15-phenyl)piperazin- 1 -y1]-8 -nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 244-(2-R14,6-R15-phenyl)piperazin-1-y1]-8-nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 244-(3-R14,5-R15-phenyl)piperazin-1-y1]-8-nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 2-[benzyl(methyl)amino]-8-nitro-6-R2-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-R2-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-chloro-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-fluoro-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-R1-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R1, R5, R14 and R15 have the above meanings.The present invention is even more particularly concerned with at least one compound selected from the group consisting of =
- 4 -2-[4-(4-Chlorophenyl)piperazin-l-y1]-6,8-dinitro-4H-1,3 -benzothiazin-4-one, 2-[4-(5-chloro-2-methylphenyl)piperazin-l-y1]-8-nitro-6-(trifluorome-thyl)-4H-1,3-benzothiazin-4-one, 8-Nitro-6-(trifluoromethyl)-2- {4- [3-(trifluoromethyl)phenyl]pip erazin-1-yl } -4H-1,3-benzothiazin-4-one, 2-[B enzyl(ethyl)amino]-8 -nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, 2-[B enzyl (methypamino]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, 2-[4-(2-Fluorophenyl)piperazin-l-y1]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, 2-(4-Benzylpiperazin-l-y1)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzo-thiazin-4-one, 2-(B enzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, 2- {Methyl [(1R)-1-phenylethyl] amino -8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, 2- [B enzyl(methypamino]-6-chloro-8 -nitro-4H-1,3 -benzothi azin-4-one.
We used 4 different methods for the synthesis of new and novel 1,3-benzothiazin-4-one derivatives. Methods A, B and C propose to use as starting material well known polysubstituted 2-chloro(bromo)-benzcarboxamides, many of them described in the literature or can be easily prepared by analogues methods (Isaew S. G. Farm. Zh. (Kiev), 2000, 52; Makosza M., Nizamov S. Org. Prep. and Proced. Int., 1997, 29, 707; Nerin C., Tomes A. R., Domento C., Cacho J. J. Agr. and Food Chem., 1996, 44, 4009; Thiel W., Mayer R., Jauer E.-A., Modrow H., Dost H. J. Prakt. Chem., 1986, 328, 497; Yokoyama M., Yoshida S., Imamoto T. Synthesis, 1982, 591; Romanowski J., Eckstein Z. Pol. J.
Chem., 1984, 58, 263; Nisato D., Sacilotto R., Frigerio M., Boveri S., Palmisano G., Lesma G. Org. Prep. Proced. Int., 1985, 17, 75; Oikawa N., Nakagawa Y., Nishimura K., Ueno T., Fujita T., Pestic. Sci., 1994, 41, 139; Welch D.E., Baron R.R., J. Med. Chem., 1969, 12, 299; Fuller R.W., Molloy B.B., Day W.A., Roush B.W., March M.M., J. Med.
Chem., 1973, 16, 101 and many others).
R13 are, independently of each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, Rp3 and K
together, R12 and R13 together represent a linear or branched aliphatic bivalent radical having 1-7 chain members;
R14 and R15 are, independently of each other, H, linear or branched aliphatic radical having 1-5 chain members, F, Cl, Br, NO2, NH2, CF3.
In a preferred embodiment the invention concerns compounds of the formula (I) selected from the group consisting of 2-[4-(2-R14,5-R15-phenyl)piperazin- 1 -y1]-8 -nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 244-(2-R14,6-R15-phenyl)piperazin-1-y1]-8-nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 244-(3-R14,5-R15-phenyl)piperazin-1-y1]-8-nitro-6-(trifluoromethyl)-4H--1,3-benzothiazin-4-one, 2-[benzyl(methyl)amino]-8-nitro-6-R2-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-R2-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-chloro-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-nitro-6-fluoro-4H-1,3-benzothiazin-4-one, 2-[benzyl(R5)amino]-8-R1-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R1, R5, R14 and R15 have the above meanings.The present invention is even more particularly concerned with at least one compound selected from the group consisting of =
- 4 -2-[4-(4-Chlorophenyl)piperazin-l-y1]-6,8-dinitro-4H-1,3 -benzothiazin-4-one, 2-[4-(5-chloro-2-methylphenyl)piperazin-l-y1]-8-nitro-6-(trifluorome-thyl)-4H-1,3-benzothiazin-4-one, 8-Nitro-6-(trifluoromethyl)-2- {4- [3-(trifluoromethyl)phenyl]pip erazin-1-yl } -4H-1,3-benzothiazin-4-one, 2-[B enzyl(ethyl)amino]-8 -nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, 2-[B enzyl (methypamino]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, 2-[4-(2-Fluorophenyl)piperazin-l-y1]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, 2-(4-Benzylpiperazin-l-y1)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzo-thiazin-4-one, 2-(B enzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, 2- {Methyl [(1R)-1-phenylethyl] amino -8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, 2- [B enzyl(methypamino]-6-chloro-8 -nitro-4H-1,3 -benzothi azin-4-one.
We used 4 different methods for the synthesis of new and novel 1,3-benzothiazin-4-one derivatives. Methods A, B and C propose to use as starting material well known polysubstituted 2-chloro(bromo)-benzcarboxamides, many of them described in the literature or can be easily prepared by analogues methods (Isaew S. G. Farm. Zh. (Kiev), 2000, 52; Makosza M., Nizamov S. Org. Prep. and Proced. Int., 1997, 29, 707; Nerin C., Tomes A. R., Domento C., Cacho J. J. Agr. and Food Chem., 1996, 44, 4009; Thiel W., Mayer R., Jauer E.-A., Modrow H., Dost H. J. Prakt. Chem., 1986, 328, 497; Yokoyama M., Yoshida S., Imamoto T. Synthesis, 1982, 591; Romanowski J., Eckstein Z. Pol. J.
Chem., 1984, 58, 263; Nisato D., Sacilotto R., Frigerio M., Boveri S., Palmisano G., Lesma G. Org. Prep. Proced. Int., 1985, 17, 75; Oikawa N., Nakagawa Y., Nishimura K., Ueno T., Fujita T., Pestic. Sci., 1994, 41, 139; Welch D.E., Baron R.R., J. Med. Chem., 1969, 12, 299; Fuller R.W., Molloy B.B., Day W.A., Roush B.W., March M.M., J. Med.
Chem., 1973, 16, 101 and many others).
- 5 -3 Cl excess NaSC(S)NR5R6 or addition light alkaly Method B Method A NaSC(S)NR5R6 R3 S N ,R5 _________________________________________________ 0 Method A
The starting 2-chlorobenzcarboxamides were treated by 1,0-1,2 equimolar quantity of the metal salts of dithiocarbamates in alcohols, aceton or in their mixture under 0-50 C for a period of about one quater of an hour to about 24 hours. Preferably, this reaction is conducted in alcohol at room temperature. The reaction mixture was diluted by water and solid 2-dithiocarbamoylbenzcarboxamide was filtered off. For the io next step it is possible to use crude product or to recrystallize it from a suitable organic solvent. 2-Dithiocarbamoylbenzcarboxamide was treated by light alkaly (e.g. Na2HPO4, NaHCO3, Na2CO3, etc) in water, alcohols or in a mixture of water/alcohol at a temperature of 50-100 C
for 2-36 hours. Preferably, this reaction is conducted in a mixture of is water/alcohol at 50-75 C for about 24 hours. When the reaction is complete, the 2-substituted-4H-1,3-benzothiazin-4-one is obtained by conventional recovery procedures, e.g. trituration with ethylacetate or dilution with water, filtration and recrystallization from a suitable organic solvent.
Method B
This method proposes to use excess of metal dithiocarbamate as light alkaly in the benzothiazinone cyclization and not to isolate 2-dithiocarbamoylbenzcarboxamide. So, the starting 2-
The starting 2-chlorobenzcarboxamides were treated by 1,0-1,2 equimolar quantity of the metal salts of dithiocarbamates in alcohols, aceton or in their mixture under 0-50 C for a period of about one quater of an hour to about 24 hours. Preferably, this reaction is conducted in alcohol at room temperature. The reaction mixture was diluted by water and solid 2-dithiocarbamoylbenzcarboxamide was filtered off. For the io next step it is possible to use crude product or to recrystallize it from a suitable organic solvent. 2-Dithiocarbamoylbenzcarboxamide was treated by light alkaly (e.g. Na2HPO4, NaHCO3, Na2CO3, etc) in water, alcohols or in a mixture of water/alcohol at a temperature of 50-100 C
for 2-36 hours. Preferably, this reaction is conducted in a mixture of is water/alcohol at 50-75 C for about 24 hours. When the reaction is complete, the 2-substituted-4H-1,3-benzothiazin-4-one is obtained by conventional recovery procedures, e.g. trituration with ethylacetate or dilution with water, filtration and recrystallization from a suitable organic solvent.
Method B
This method proposes to use excess of metal dithiocarbamate as light alkaly in the benzothiazinone cyclization and not to isolate 2-dithiocarbamoylbenzcarboxamide. So, the starting 2-
- 6 -chlorobenzcarboxamides can be treated with a 1,2-2,5 equimolar quantity of the metal salts of dithiocarbamates in alcohols, aceton or in their mixture at 20-80 C for a period of about 3-36 hours. Preferably, this reaction is conducted in alcohol or in a mixture of water/alcohol at 50-75 C for about 24 hours. The aimed 2-substituted-4H-1,3-benzothiazin-4-one is obtained by recovery procedures from method A.
Method C
R3 CI R3 SOAlk CD KSC(S)0Alk 0 r R3 S N, Method C
This method uses as starting material 2-chlorobenzencarboxamides.
These compounds were treated with 1,1-2,0 fold excess of metal salts of alkylxantogenate, for example commercial available potassium ethylxantogenate, at a temperature of 20-100 C in different alcohols, acetone, acetonitrile or other suitable organic solvents for a period of about one half hour to about 24 hours. Preferably, this reaction is conducted in alcohol at room temperature for about 24 hours. The isolated 2-alkoxy-4H-1,3-benzothiazin-4-one was treated with the corresponding amine HNR5R6 in acetic acid, alcohols, ethylacetate, DMF, aceton or acetonitril for a period of up to 48 hours for full exchange of the alkoxy group to the corresponding amine. After the process is completed the reaction mixture can be evaporated and diluted by water or it can be diluted by water directly. The aimed 2- NR5R6-4H-1,3-benzothiazin-4-one is recovered by customary isolation procedures, e.g. filtration and recrystallization from a suitable organic solvent.
Method C
R3 CI R3 SOAlk CD KSC(S)0Alk 0 r R3 S N, Method C
This method uses as starting material 2-chlorobenzencarboxamides.
These compounds were treated with 1,1-2,0 fold excess of metal salts of alkylxantogenate, for example commercial available potassium ethylxantogenate, at a temperature of 20-100 C in different alcohols, acetone, acetonitrile or other suitable organic solvents for a period of about one half hour to about 24 hours. Preferably, this reaction is conducted in alcohol at room temperature for about 24 hours. The isolated 2-alkoxy-4H-1,3-benzothiazin-4-one was treated with the corresponding amine HNR5R6 in acetic acid, alcohols, ethylacetate, DMF, aceton or acetonitril for a period of up to 48 hours for full exchange of the alkoxy group to the corresponding amine. After the process is completed the reaction mixture can be evaporated and diluted by water or it can be diluted by water directly. The aimed 2- NR5R6-4H-1,3-benzothiazin-4-one is recovered by customary isolation procedures, e.g. filtration and recrystallization from a suitable organic solvent.
- 7 -Method D
The classical method of 1,3-benzothiazin-4-one synthesis by use of the reaction of thiocyanate salts with 2-chloroarylchloroanhydride and a subsequent treatment of the reaction mass with the corresponding amine is usable too. This method is well described in the scientific literature, for example: J. Imrich, P. Kristian, Coll. Czech. Chem. Commun., 1982, 47, 3268-3282; D. Koscik, P. Kristian, J. Gonda, E. Dandarova, Coll. Czech. Chem. Commun., 1983, 48, 3315-3328; D. Koscik, P. Kristian, 0. Forgac, Coll. Czech. Chem. Commun., 1983, 48, 3427-3432; T. H. Cronin, H. ¨ J .E. Hess, Pat. US 3522247.
Surprisingly the compounds of the invention exhibit strong antibacterial activity, especially against mycobacteria with minimal inhibitory concentrations (MIC) in the range of <0,000012 - 0,78 p.g/m1 for fast growing mycobacteria, of <0.39 - 3.12 ptg/m1 for M. tuberculosis, including multiresistant strains, determined by the classical method and of 2.0 ¨ 50.0 ng/ml for M tuberculosis H37Rv determined by the Alamar Blue method. Surprisingly the compounds of the invention demonstrate a high level of selectivity for mycobacteria only which reduces the potential for adverse side effects dramatically.
The compounds of the invention are non-mutagenic at 5 mg/ml in the SOS chromotest (M.Isidori, M. Lavorgna, A.Nardelli, L.Pascarella, A.
Parella, Sci. Total Environ., 2005, 346, 87-98; M. Bombardier, N.
Bermingham, R. Legault, A. Fouquet, Chemosphere, 2001, 42, 931-44;
D.A. Widdick, D.I. Edwards, Mutat. Res., 1991, 259, 89-93).
Thus, the compounds of the invention are useful for the treatment of tuberculosis infections and other mycobacterial infections, in humans and in animals.
Accordingly, the invention concerns pharmaceutical compositions comprising a compound of the formula I.
The invention relates furthermore to a compound of the formula I for use in a method for the treatment of bacterial infections in mammals.
The classical method of 1,3-benzothiazin-4-one synthesis by use of the reaction of thiocyanate salts with 2-chloroarylchloroanhydride and a subsequent treatment of the reaction mass with the corresponding amine is usable too. This method is well described in the scientific literature, for example: J. Imrich, P. Kristian, Coll. Czech. Chem. Commun., 1982, 47, 3268-3282; D. Koscik, P. Kristian, J. Gonda, E. Dandarova, Coll. Czech. Chem. Commun., 1983, 48, 3315-3328; D. Koscik, P. Kristian, 0. Forgac, Coll. Czech. Chem. Commun., 1983, 48, 3427-3432; T. H. Cronin, H. ¨ J .E. Hess, Pat. US 3522247.
Surprisingly the compounds of the invention exhibit strong antibacterial activity, especially against mycobacteria with minimal inhibitory concentrations (MIC) in the range of <0,000012 - 0,78 p.g/m1 for fast growing mycobacteria, of <0.39 - 3.12 ptg/m1 for M. tuberculosis, including multiresistant strains, determined by the classical method and of 2.0 ¨ 50.0 ng/ml for M tuberculosis H37Rv determined by the Alamar Blue method. Surprisingly the compounds of the invention demonstrate a high level of selectivity for mycobacteria only which reduces the potential for adverse side effects dramatically.
The compounds of the invention are non-mutagenic at 5 mg/ml in the SOS chromotest (M.Isidori, M. Lavorgna, A.Nardelli, L.Pascarella, A.
Parella, Sci. Total Environ., 2005, 346, 87-98; M. Bombardier, N.
Bermingham, R. Legault, A. Fouquet, Chemosphere, 2001, 42, 931-44;
D.A. Widdick, D.I. Edwards, Mutat. Res., 1991, 259, 89-93).
Thus, the compounds of the invention are useful for the treatment of tuberculosis infections and other mycobacterial infections, in humans and in animals.
Accordingly, the invention concerns pharmaceutical compositions comprising a compound of the formula I.
The invention relates furthermore to a compound of the formula I for use in a method for the treatment of bacterial infections in mammals.
- 8 -Preferred compounds of the formula I for use in such method are those specifically listed above.
The compounds of the invention are formulated for use by preparing a diluted solution or suspension in pharmaceutically acceptable aqueous, organic or aqueous-organic medium for topical or parenteral administration by intravenous, subcutaneous or intramuscular injection, or for intranasal application; or are prepared in tablet, capsule or aqueous suspension form with conventional excipients for oral administration or io as suppositorium.
The compounds can be used in dosages from 0.001 ¨ 1000 mg/kg body weight.
The examples which follow in the subsequent experimental part serve to illustrate the invention but should not be construed as a limitation thereof.
The structures of the compounds of the invention were established by modes of synthesis and elementary analysis, and by nuclear magnetic resonance and mass spectra.
Embodiments Starting materials Chemicals and solvents were purchased from Alfa-Aesar (GB) or from Aldrich Co. (Sigma-Aldrich Company, St-Louis, US) and were used in the synthesis without additional purification. Melting points were determined according to the BP procedure and are uncorrected (Electrothermal 9001, GB). If analyses are indicated only by the symbols of the elements, analytical results are within 0.3% of the theoretical values (Carlo-Erba 5500, Italy). NMR spectra were determined with a Varian Unity Plus 400 (USA). Shifts for 11-I NMR are reported in ppm downfield from TMS (8). Mass spectra were obtained using a Finnigan SSQ-700 (USA) instrument with direct injection. Reactions and purity of
The compounds of the invention are formulated for use by preparing a diluted solution or suspension in pharmaceutically acceptable aqueous, organic or aqueous-organic medium for topical or parenteral administration by intravenous, subcutaneous or intramuscular injection, or for intranasal application; or are prepared in tablet, capsule or aqueous suspension form with conventional excipients for oral administration or io as suppositorium.
The compounds can be used in dosages from 0.001 ¨ 1000 mg/kg body weight.
The examples which follow in the subsequent experimental part serve to illustrate the invention but should not be construed as a limitation thereof.
The structures of the compounds of the invention were established by modes of synthesis and elementary analysis, and by nuclear magnetic resonance and mass spectra.
Embodiments Starting materials Chemicals and solvents were purchased from Alfa-Aesar (GB) or from Aldrich Co. (Sigma-Aldrich Company, St-Louis, US) and were used in the synthesis without additional purification. Melting points were determined according to the BP procedure and are uncorrected (Electrothermal 9001, GB). If analyses are indicated only by the symbols of the elements, analytical results are within 0.3% of the theoretical values (Carlo-Erba 5500, Italy). NMR spectra were determined with a Varian Unity Plus 400 (USA). Shifts for 11-I NMR are reported in ppm downfield from TMS (8). Mass spectra were obtained using a Finnigan SSQ-700 (USA) instrument with direct injection. Reactions and purity of
- 9 -compounds were controlled by TLC using Silicagel 60 F254 aluminium sheets (Merck Co, Germany).
Example 1 2-[4-(4-Chlorophenyl)piperazin-l-y1]-6,8-dinitro-4H-1,3 -benzothi azin-4-one, (compound 1) 0.5 g of 2-chloro-3,5-dinitrobenzcarboxamide was dissolved in 25 ml ethanol. The reaction mixture was treated with of 0.39 g of 4-(4-chloropheny1)-piperazine dithiocarbamate sodium salt dihydrate and stored for 6 h at room temperature. The reaction mixture was poured into 50 ml of cooled water and the resulting yellow precipitate was filtered off. Pure final product was obtained after recrystallization from ethanol.
s 2-Amino carbony1-4,6-dinitropheny1-4-(4-chlorophenyl)piperazine-1 -carbodithioate is a light yellow crystalline solid. Yield 68 %. mp 178-180 C. MS m/z 481 (MI).
Anal. Calcd. for C18H16C1N505S2: C, 44.86; H, 3.35; N, 14.53; S, 13.31 Found: C, 44.71; H, 3.36; N, 14.62; S, 13.35 0.5 g of 2-aminocarbony1-4,6-dinitropheny1-4-(4-chlorophenyl)pipe-razine- 1 -carbodithioate was dissolved in 25 ml ethanol. The reaction mixture was treated with of 0.2 g of Na2HPO4 x 12H20 and refluxed for 6 h. Reaction mixture was cooled in the refrigerator and the ligth yellow precipitate was filtered off and washed with 50 ml water and 30 ml methanol. Pure final product was obtained after recrystallization twice from ethanol. 2-(1,4-2-[4-(4-Chlorophenyppiperazin-1-y1]-6,8-dinitro-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 38 %. mp 279-281 C (Et0H) MS m/z 447 (M+).
1H NMR (DMSO-d6/CDC13) 5 9.08 and 8.95 (two 1H, two s, 2CH), 6.88 and 6.71 (two 2H, d, C6H4C1), 3,68 and 3.30 (two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for C18H14C1N505S: C, 48.27; H, 3.15; N, 15.04; S, 7.16 Found: C, 48.34; H, 3.22; N, 14.97; S, 7.23
Example 1 2-[4-(4-Chlorophenyl)piperazin-l-y1]-6,8-dinitro-4H-1,3 -benzothi azin-4-one, (compound 1) 0.5 g of 2-chloro-3,5-dinitrobenzcarboxamide was dissolved in 25 ml ethanol. The reaction mixture was treated with of 0.39 g of 4-(4-chloropheny1)-piperazine dithiocarbamate sodium salt dihydrate and stored for 6 h at room temperature. The reaction mixture was poured into 50 ml of cooled water and the resulting yellow precipitate was filtered off. Pure final product was obtained after recrystallization from ethanol.
s 2-Amino carbony1-4,6-dinitropheny1-4-(4-chlorophenyl)piperazine-1 -carbodithioate is a light yellow crystalline solid. Yield 68 %. mp 178-180 C. MS m/z 481 (MI).
Anal. Calcd. for C18H16C1N505S2: C, 44.86; H, 3.35; N, 14.53; S, 13.31 Found: C, 44.71; H, 3.36; N, 14.62; S, 13.35 0.5 g of 2-aminocarbony1-4,6-dinitropheny1-4-(4-chlorophenyl)pipe-razine- 1 -carbodithioate was dissolved in 25 ml ethanol. The reaction mixture was treated with of 0.2 g of Na2HPO4 x 12H20 and refluxed for 6 h. Reaction mixture was cooled in the refrigerator and the ligth yellow precipitate was filtered off and washed with 50 ml water and 30 ml methanol. Pure final product was obtained after recrystallization twice from ethanol. 2-(1,4-2-[4-(4-Chlorophenyppiperazin-1-y1]-6,8-dinitro-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 38 %. mp 279-281 C (Et0H) MS m/z 447 (M+).
1H NMR (DMSO-d6/CDC13) 5 9.08 and 8.95 (two 1H, two s, 2CH), 6.88 and 6.71 (two 2H, d, C6H4C1), 3,68 and 3.30 (two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for C18H14C1N505S: C, 48.27; H, 3.15; N, 15.04; S, 7.16 Found: C, 48.34; H, 3.22; N, 14.97; S, 7.23
- 10 -Example 2 2-[4-(5-chloro-2-methylphenyl)piperazin-l-yl] -8-nitro-6-(trifluorome-thyl)-4H-1,3 -benzothiazin-4-one, (compound 2) Following the procedure of Example 1 using of 2-chloro-3-nitro-5-trifluoromethylbenzcarboxamide as starting material. Light yellow crystalline solid. Yield 44%. mp 158-161 C (DMF/water) MS m/z 484 (M+).
NMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.32 (1H, s, CH), 9.95 and 6.73 (two 1H, d, two CH), 3,65 and 3.29 ( two 4H, m, N(CH2CH2)2N), 2.29 (3H, s, CH3) PPm=
Anal. Calcd. for C20Hi6C1F3N403S: C, 49.54; H, 3.33; N, 11.55; S, 6.61 Found: C, 49.45; H, 3.40; N, 11.47; S, 6.83 Example 3 8-Nitro-6-(trifluoromethyl)-2- {4-[3-(trifluoromethyl)phenyl]piperazin-1-yll -4H-1,3-benzothiazin-4-one, (compound 3) Following the procedure of Example 1 using of 2-chloro-3-nitro-5-trifluoromethylbenzcarboxamide as starting material. Light yellow crystaline solid. Yield 33%. mp 201-203 C (Et0H).
MS m/z 504 (MI).
1HNMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.61 (1H, s, CH), 7.39 and 7.03 (two 1H, d, two CH), 3,66 and 3.31 ( two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for C20H14F6N403S: C, 47.62; H, 2.80; N, 11.11; S, 6.36 Found: C, 47.74; H, 2.91; N, 11.29; S, 6.53 Example 4 2-[B enzyl(ethyl)amino] -8 -nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, (compound 4) A suspension of 1.2 g 2-chloro-3-amino-5-trifluoromethyl-benzcarboxamide in 45 ml ethanol was treated with 2.0 g of benzyl(ethyl)dithiocarbamate sodium salt dihydrate and refluxed for 14 h. The dark red reaction mixture was diluted with 70 ml of water, cooled in the refrigerator for 6 hours, the ligth yellow precipitate was filtered off and washed with 50 ml ester. Pure final product was obtained after
NMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.32 (1H, s, CH), 9.95 and 6.73 (two 1H, d, two CH), 3,65 and 3.29 ( two 4H, m, N(CH2CH2)2N), 2.29 (3H, s, CH3) PPm=
Anal. Calcd. for C20Hi6C1F3N403S: C, 49.54; H, 3.33; N, 11.55; S, 6.61 Found: C, 49.45; H, 3.40; N, 11.47; S, 6.83 Example 3 8-Nitro-6-(trifluoromethyl)-2- {4-[3-(trifluoromethyl)phenyl]piperazin-1-yll -4H-1,3-benzothiazin-4-one, (compound 3) Following the procedure of Example 1 using of 2-chloro-3-nitro-5-trifluoromethylbenzcarboxamide as starting material. Light yellow crystaline solid. Yield 33%. mp 201-203 C (Et0H).
MS m/z 504 (MI).
1HNMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.61 (1H, s, CH), 7.39 and 7.03 (two 1H, d, two CH), 3,66 and 3.31 ( two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for C20H14F6N403S: C, 47.62; H, 2.80; N, 11.11; S, 6.36 Found: C, 47.74; H, 2.91; N, 11.29; S, 6.53 Example 4 2-[B enzyl(ethyl)amino] -8 -nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, (compound 4) A suspension of 1.2 g 2-chloro-3-amino-5-trifluoromethyl-benzcarboxamide in 45 ml ethanol was treated with 2.0 g of benzyl(ethyl)dithiocarbamate sodium salt dihydrate and refluxed for 14 h. The dark red reaction mixture was diluted with 70 ml of water, cooled in the refrigerator for 6 hours, the ligth yellow precipitate was filtered off and washed with 50 ml ester. Pure final product was obtained after
- 11 -column chromatography (hexane/aceton 3:1). 2-[Benzyl(ethyl)amino]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothia-zin-4-one is a light yellow crystalline solid. Yield 40 %. mp 94-97 C.
MS m/z 409 (Mt).
111 NMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.41-7.25 (5H, m, C6H5), 4.62 (2H, s, CH2), 3.43 (2H, q, CH2), 1.01 (3H, t, CH3) ppm.
Anal. Calcd. for CHHI4F3N303S: C, 52.81; H, 3.45; N, 10.26; S, 7.83 Found: C, 52.73; H, 3.38; N, 10.44; S, 7.89 Example 5 2- [B enzyl(methypamino]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, (compound 5) Following the procedure of Example 4. Light yellow crystalline solid.
Yield 47%. mp 120-124 C (Et0H/water).
MS m/z 395 (Mt).
11-1 NMR (DMSO-d6/CDC13) 6 8.81 and 8.77 (two 1H, two s, 2CH), 7.40-7.25 (5H, m, C6H5), 4.64 (2H, s, CH2), 2.87 (3H, s, CH3) PPm=
Anal. Calcd. for CI7H12F3N303S: C, 51.64; H, 3.06; N, 10.63; S, 8.11 Found: C, 51.76; H, 3.13; N, 10.41;
S, 8.34 Example 6 2- [4-(2-Fluorophenyl)pip erazin-l-y1]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, (compound 6) Following the procedure of Example 1. Light yellow crystalline solid.
Yield 37%. mp 164-168 C (i-PrOH).
MS m/z 454 (Mt).
'H NMR (DMSO-d6/CDC13) 6 8.81 and 8.77 (two 1H, two s, 2CH), 6.76 (3H, m, 3CH), 6.11 (1H, m, CH), 3,68 and 3.30 (two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for Ci9H14F4N403S: C, 50.22; H, 3.11; N, 12.33; S, 7.06 Found: C, 50.08; H, 3.21; N, 12.46; S, 7.09 Example 7 2-(4-Benzylpiperazin-l-y1)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzo-thiazin-4-one, (compound 7)
MS m/z 409 (Mt).
111 NMR (DMSO-d6/CDC13) 6 8.80 and 8.77 (two 1H, two s, 2CH), 7.41-7.25 (5H, m, C6H5), 4.62 (2H, s, CH2), 3.43 (2H, q, CH2), 1.01 (3H, t, CH3) ppm.
Anal. Calcd. for CHHI4F3N303S: C, 52.81; H, 3.45; N, 10.26; S, 7.83 Found: C, 52.73; H, 3.38; N, 10.44; S, 7.89 Example 5 2- [B enzyl(methypamino]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothia-zin-4-one, (compound 5) Following the procedure of Example 4. Light yellow crystalline solid.
Yield 47%. mp 120-124 C (Et0H/water).
MS m/z 395 (Mt).
11-1 NMR (DMSO-d6/CDC13) 6 8.81 and 8.77 (two 1H, two s, 2CH), 7.40-7.25 (5H, m, C6H5), 4.64 (2H, s, CH2), 2.87 (3H, s, CH3) PPm=
Anal. Calcd. for CI7H12F3N303S: C, 51.64; H, 3.06; N, 10.63; S, 8.11 Found: C, 51.76; H, 3.13; N, 10.41;
S, 8.34 Example 6 2- [4-(2-Fluorophenyl)pip erazin-l-y1]-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, (compound 6) Following the procedure of Example 1. Light yellow crystalline solid.
Yield 37%. mp 164-168 C (i-PrOH).
MS m/z 454 (Mt).
'H NMR (DMSO-d6/CDC13) 6 8.81 and 8.77 (two 1H, two s, 2CH), 6.76 (3H, m, 3CH), 6.11 (1H, m, CH), 3,68 and 3.30 (two 4H, m, N(CH2CH2)2N) ppm.
Anal. Calcd. for Ci9H14F4N403S: C, 50.22; H, 3.11; N, 12.33; S, 7.06 Found: C, 50.08; H, 3.21; N, 12.46; S, 7.09 Example 7 2-(4-Benzylpiperazin-l-y1)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzo-thiazin-4-one, (compound 7)
- 12 -Following the procedure of Example 4. Yellow crystalline solid. Yield 51%. mp 161-163 C (Et0H/DMF).
MS m/z 450 (MI).
111 NMR (DMSO-d6/CDC13) 5 8.80 and 8.76 (two 1H, two s, 2CH), 7.19-7.28 (5H, m, Ph), 3.48 (2H, s, CH2), 3,38 and 3.09 (two 4H, m, N(CH2CH2)2N) PPIn=
Anal. Calcd. for Ci7H18N407S: C, 53.33; H, 3.80; N, 12.44; S, 7.12 Found: C, 53.29; H, 4.01; N, 12.48; S, 7.06 o Example 8 2-(B enzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, (compound 8) A suspension of 2.5 g 2-chloro-3-nitro-5-trifluoromethylbenzcar-boxamide in 25 ml ethanol was treated with of 1.75 g of sodium ethylxantogenate and stored for 24 h at room temperature. The reaction mixture was poured into 50 ml of cooled water and the resulting yellow precipitate was filtered off. Pure 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one was obtained after recrystallization from ethanol/water as white crystalline solid. Yield 58 %. mp 146-148 C.
MS m/z 320 (Mt).
Anal. Calcd. for CI IH7F3N204S: C, 41.26; H, 2.20; N, 8.75; S, 10.01 Found: C, 41.34; H, 2.22; N, 8.87; S, 10.27 A solution of 0.7 g of 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one in 15 ml acetic acid was treated with 0.4 ml of benzylamine and refluxed for 14 h. The reaction mixture was evaporated and the residue was treated by 10 ml water, the yellow precipitate was filtered off and washed with 50 ml water. Pure final product was obtained after recrystallization twice from ethanol/DMF. 2-(Benzylamino)-8 -nitro - 6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 73 %. mp 192-194 C.
MS m/z 381 (Mt).
NMR (DMSO-d6/CDC13) 5 9.27 (1H, broad s, NH), 8.80 and 8.75 (two 1H, two s, 2CH), 7.74-7.49 (5H, m, Ph), 4.49 (2H, s, CH2) PPni=
MS m/z 450 (MI).
111 NMR (DMSO-d6/CDC13) 5 8.80 and 8.76 (two 1H, two s, 2CH), 7.19-7.28 (5H, m, Ph), 3.48 (2H, s, CH2), 3,38 and 3.09 (two 4H, m, N(CH2CH2)2N) PPIn=
Anal. Calcd. for Ci7H18N407S: C, 53.33; H, 3.80; N, 12.44; S, 7.12 Found: C, 53.29; H, 4.01; N, 12.48; S, 7.06 o Example 8 2-(B enzylamino)-8-nitro-6-(trifluoromethyl)-4H-1,3 -benzothiazin-4-one, (compound 8) A suspension of 2.5 g 2-chloro-3-nitro-5-trifluoromethylbenzcar-boxamide in 25 ml ethanol was treated with of 1.75 g of sodium ethylxantogenate and stored for 24 h at room temperature. The reaction mixture was poured into 50 ml of cooled water and the resulting yellow precipitate was filtered off. Pure 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one was obtained after recrystallization from ethanol/water as white crystalline solid. Yield 58 %. mp 146-148 C.
MS m/z 320 (Mt).
Anal. Calcd. for CI IH7F3N204S: C, 41.26; H, 2.20; N, 8.75; S, 10.01 Found: C, 41.34; H, 2.22; N, 8.87; S, 10.27 A solution of 0.7 g of 2-ethoxy-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one in 15 ml acetic acid was treated with 0.4 ml of benzylamine and refluxed for 14 h. The reaction mixture was evaporated and the residue was treated by 10 ml water, the yellow precipitate was filtered off and washed with 50 ml water. Pure final product was obtained after recrystallization twice from ethanol/DMF. 2-(Benzylamino)-8 -nitro - 6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one is a light yellow crystalline solid. Yield 73 %. mp 192-194 C.
MS m/z 381 (Mt).
NMR (DMSO-d6/CDC13) 5 9.27 (1H, broad s, NH), 8.80 and 8.75 (two 1H, two s, 2CH), 7.74-7.49 (5H, m, Ph), 4.49 (2H, s, CH2) PPni=
- 13 -Anal. Calcd. for C16H10F3N303S: C, 50.39; H, 2.64; N, 11.02; S, 8.41 Found: C, 50.42; H, 2.61; N, 10.89; S, 8.64 Example 9 2- {Methyl [(1R)-1-phenylethyl]amino}-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, (compound 9) Following the procedure of Example 1. Light yellow crystalline solid.
Yield 54%. mp 110-113 C (purification by column chromatography aceton/hexane 5:1).
MS m/z 409 (M+).
Ili NMR (DMSO-d6/CDC13) 6 8.82 and 8.76 (two 1H, two s, 2CH), 7.84, 7.43, 7.15 (5H, 3 m, Ph), 4.84 (H, m, CH), 3.07 (3H, s, NCH3), 1.39 (3H, d, CH3) ppm.
Anal. Calcd. for CI8H14F3N303S: C, 52.81; H, 3.45; N, 10.26; S, 7.83 Found: C, 52.73; H, 3.46; N, 10.19; S, 7.92 Example 10 2-[Benzyl(methyl)amino]-6-chloro-8-nitro-4H-1,3-benzothiazin-4-one, (compound 10) Following the procedure of Example 8. Light yellow crystalline solid.
Yield 64%. mp 138-141 C (purification by column chromatography aceton/hexane 4:1).
MS m/z 361 (M).
111 NMR (DMSO-d6/CDC13) 6 8.37 and 8.23 (two 1H, two s, 2CH), 7.45-7.35 (5H, m, Ph), 4.62 (2H, 2, CH2), 2.87 (3H, s, CH3) PPm=
Anal. Calcd. for C16H12C1N3035: C, 53.11; H, 3.34; N, 11.61; S, 8.86 Found: C, 53.19; H, 3.30; N, 11.52; S, 8.89 Example 11 Determination of the in vitro inhibitory activity of the compounds of the invention against mycobacteria.
The antibacterial activities of the compounds against Mycobacterium smegmatis SG 987, M aurum SB66, M vaccae IMET 10670 and M
fortuitum B were tested by determination of minimal inhibitory
Yield 54%. mp 110-113 C (purification by column chromatography aceton/hexane 5:1).
MS m/z 409 (M+).
Ili NMR (DMSO-d6/CDC13) 6 8.82 and 8.76 (two 1H, two s, 2CH), 7.84, 7.43, 7.15 (5H, 3 m, Ph), 4.84 (H, m, CH), 3.07 (3H, s, NCH3), 1.39 (3H, d, CH3) ppm.
Anal. Calcd. for CI8H14F3N303S: C, 52.81; H, 3.45; N, 10.26; S, 7.83 Found: C, 52.73; H, 3.46; N, 10.19; S, 7.92 Example 10 2-[Benzyl(methyl)amino]-6-chloro-8-nitro-4H-1,3-benzothiazin-4-one, (compound 10) Following the procedure of Example 8. Light yellow crystalline solid.
Yield 64%. mp 138-141 C (purification by column chromatography aceton/hexane 4:1).
MS m/z 361 (M).
111 NMR (DMSO-d6/CDC13) 6 8.37 and 8.23 (two 1H, two s, 2CH), 7.45-7.35 (5H, m, Ph), 4.62 (2H, 2, CH2), 2.87 (3H, s, CH3) PPm=
Anal. Calcd. for C16H12C1N3035: C, 53.11; H, 3.34; N, 11.61; S, 8.86 Found: C, 53.19; H, 3.30; N, 11.52; S, 8.89 Example 11 Determination of the in vitro inhibitory activity of the compounds of the invention against mycobacteria.
The antibacterial activities of the compounds against Mycobacterium smegmatis SG 987, M aurum SB66, M vaccae IMET 10670 and M
fortuitum B were tested by determination of minimal inhibitory
- 14 -concentrations (MIC) by the broth micro dilution method in Mueller-Hinton broth (Difco) according to the NCCLS guidelines [National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; 5th Ed.; Villanova, Ed.; Approved standard Document M7-A5. NCCLS, (2000)]. The results are presented in Table 1.
Table 1: Antimicrobial activity of compounds as of the formula I
determined by minimal inhibitory concentrations MIC [ig/m1]
Compound M. smegmatis M.vaccae M.fortuitum MIC [g/m1] MIC [g/m1] MIC {g/ml]
1 0,78 0,0062 0,78 2 0,05 0,008 0,031 3 0,04 0,0031 0,0031 4 0,0062 0,0008 0,0062 5 0,0156 0,0005 0,0156 6 0,005 0,005 0,005 7 0,05 0,05 0,05 8 0,00078 <0,0000121 0,00078 9 <0,0000121 <0,0000121 <0,0000121 10 0,0062 0,00031 0,00156 Example 12 Activity against M tuberculosis H37Rv was tested by the following method for determination of minimal inhibitory concentrations (MIC) is and minimal bactericidal concentrations (MBC):
Strains were inoculated onto solid Lowenstein-Jensen medium. After 21 days, the cultures grown were used to prepare an inoculum suspension corresponding to 5 x 108 microbial cells/ml. With 0,2 ml of that suspension tubes with 2 ml liquid Shkolnikova medium, containing corresponding concentrations of compounds under study ¨ from 100,0 to 0,195 g/ml, were inoculated. After 14 days of incubation at 37 C the tubes with liquid medium were centrifuged for 15min. at 3000 RPM.
After discarding the supernatant, the sediment was resuspended in 0,8 ml of sterile 0,9% NaCl. 0,1 ml of the suspension was used to prepare smears subsequently stained by the Ziehl-Neelsen method. The
Table 1: Antimicrobial activity of compounds as of the formula I
determined by minimal inhibitory concentrations MIC [ig/m1]
Compound M. smegmatis M.vaccae M.fortuitum MIC [g/m1] MIC [g/m1] MIC {g/ml]
1 0,78 0,0062 0,78 2 0,05 0,008 0,031 3 0,04 0,0031 0,0031 4 0,0062 0,0008 0,0062 5 0,0156 0,0005 0,0156 6 0,005 0,005 0,005 7 0,05 0,05 0,05 8 0,00078 <0,0000121 0,00078 9 <0,0000121 <0,0000121 <0,0000121 10 0,0062 0,00031 0,00156 Example 12 Activity against M tuberculosis H37Rv was tested by the following method for determination of minimal inhibitory concentrations (MIC) is and minimal bactericidal concentrations (MBC):
Strains were inoculated onto solid Lowenstein-Jensen medium. After 21 days, the cultures grown were used to prepare an inoculum suspension corresponding to 5 x 108 microbial cells/ml. With 0,2 ml of that suspension tubes with 2 ml liquid Shkolnikova medium, containing corresponding concentrations of compounds under study ¨ from 100,0 to 0,195 g/ml, were inoculated. After 14 days of incubation at 37 C the tubes with liquid medium were centrifuged for 15min. at 3000 RPM.
After discarding the supernatant, the sediment was resuspended in 0,8 ml of sterile 0,9% NaCl. 0,1 ml of the suspension was used to prepare smears subsequently stained by the Ziehl-Neelsen method. The
- 15 -remaining sediment was inoculated in 0,2 ml volumes into three tubes with solid drug free Lowenstein-Jensen medium to determine minimal bactericidal concentrations (MBC). The results were read after 21-28 days of cultivation at 37 C. Controls were tubes cultured with test-s strains not treated with the studied agents.
Minimal bactericidal concentration of drugs (MBC) was considered as the drug concentration completely inhibiting the growth of mycobacteria on the solid medium. The bacteriostatic effect (MIC) was characterized by the presence of only individual mycobacteria in the smear and a strong decrease in the number of colonies grown on solid media compared to the controls. The results are presented in Table 2.
Table 2: Antimicrobial activity of compounds of the formula I against Mycobacterium tuberculosis H37Rv and clinical isolates HSRE resistant strain and XTB strain as determined by minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) Strain Compound MBC MIC
= (tig/mL) ( g/mL) H37Rv 3.12 1.56 HSRE resistant 5 3.12 1.56 XTB 3.12 1.56 H37Rv 1.56 1.56 HSRE resistant 8 1.56 0.78 XTB 1.56 0.78 H37Rv 0.78 <0.39 HSRE resistant 10 1.56 1.56 X TB 0.39 <0.39 H37Rv 1.56 0.78 HSRE resistant Isoniazid (INH) Not active X TB Not active HSRE: multiresistant strain XTB: extremly resistant strain Example 13 Activity against M tuberculosis H37Rv was determined by the resazurin reduction assay (MIC96) too. The method was described in detail in: P.
Quillardet, 0. Huisman, R. D'Ari, M. Hofnung, Proc. Natl. Acad. Sci.
USA, 1982, 79, 5971-5; J.C. Palomino, A. Martin, M. Camacho, H.
Guerra, J. Swings, F. Portaels, Antimicrob. Agents Chemother., 2002, 46, 2720-2. The results are presented in Table 3.
Minimal bactericidal concentration of drugs (MBC) was considered as the drug concentration completely inhibiting the growth of mycobacteria on the solid medium. The bacteriostatic effect (MIC) was characterized by the presence of only individual mycobacteria in the smear and a strong decrease in the number of colonies grown on solid media compared to the controls. The results are presented in Table 2.
Table 2: Antimicrobial activity of compounds of the formula I against Mycobacterium tuberculosis H37Rv and clinical isolates HSRE resistant strain and XTB strain as determined by minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) Strain Compound MBC MIC
= (tig/mL) ( g/mL) H37Rv 3.12 1.56 HSRE resistant 5 3.12 1.56 XTB 3.12 1.56 H37Rv 1.56 1.56 HSRE resistant 8 1.56 0.78 XTB 1.56 0.78 H37Rv 0.78 <0.39 HSRE resistant 10 1.56 1.56 X TB 0.39 <0.39 H37Rv 1.56 0.78 HSRE resistant Isoniazid (INH) Not active X TB Not active HSRE: multiresistant strain XTB: extremly resistant strain Example 13 Activity against M tuberculosis H37Rv was determined by the resazurin reduction assay (MIC96) too. The method was described in detail in: P.
Quillardet, 0. Huisman, R. D'Ari, M. Hofnung, Proc. Natl. Acad. Sci.
USA, 1982, 79, 5971-5; J.C. Palomino, A. Martin, M. Camacho, H.
Guerra, J. Swings, F. Portaels, Antimicrob. Agents Chemother., 2002, 46, 2720-2. The results are presented in Table 3.
- 16 -Table 3: Antimycobacterial activity of compounds as of the formula I
determined by minimal inhibitory concentrations (MIC) [ng/m1]
Compound M. tuberculosis H37Rv (ng/ml) 9 0,4
determined by minimal inhibitory concentrations (MIC) [ng/m1]
Compound M. tuberculosis H37Rv (ng/ml) 9 0,4
Claims (10)
1. A compound of formula I
or a salt thereof, wherein R1 and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONR10R11, CHO, F, CI, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
R6 is a radical:
wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals:
wherein n is 1-4:
R7-R13 are independently from each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, R10 and R11 together, R12 and R13 together represent a linear or branched aliphatic bivalent radical having 1-7 chain members;
R14 and R15 are independently from each other H, a linear or branched aliphatic radical having 1-5 chain members, F, CI, Br, NO2, NH2, or CF3.
or a salt thereof, wherein R1 and R2 are, independently of each other, NO2, NR7R8, NHOR9, COOR9, CN, CONR10R11, CHO, F, CI, Br, SO2NR12R13, lower alkoxy, OCF3, mono-, di or trifluoromethyl;
R3 and R4 are, independently of each other, H, a saturated or unsaturated, linear or branched aliphatic radical having 1-3 chain members, F, Cl, Br, lower alkoxy;
R5 is H, a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1 -7 chain members;
R6 is a radical:
wherein X is saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, or R5 and R6 together represent bivalent radicals:
wherein n is 1-4:
R7-R13 are independently from each other H or a saturated or unsaturated, halogenated or unhalogenated, linear or branched aliphatic radical having 1-5 chain members, phenyl, benzyl or R7 and R8 together, R10 and R11 together, R12 and R13 together represent a linear or branched aliphatic bivalent radical having 1-7 chain members;
R14 and R15 are independently from each other H, a linear or branched aliphatic radical having 1-5 chain members, F, CI, Br, NO2, NH2, or CF3.
2. A compound according to claim 1, selected from the group consisting of:
A) 244-(2-R14, 5-R15-Phenyppiperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R14 represents H and R15 represents F, CI, or Br, B) 2-[4-(3 -R14, 5 -R15-Phenyl)piperazin-1 -yl ]-8-nitro-6-(trifluoromethyl)-4H-1 ,3 -benzothiazin-4-one, wherein R14 represents H and R15 represents F or CI, C) 2-[Benzyl(methyl)amino]-8-nitro-6-R2-4H-1, 3-benzothiazin-4-one, wherein R2 represents CF3, Cl or F, D) 2-[Benzyl(R5)amino]-8 -R1 -6-(trifluoromethyl)-4H-1,3- benzothiazin-4-one, wherein R1 represents CF3, NO2, NHOH or NR7R8 and R5, R7 and R8 have the same meaning as defined in claim 1, E) 6-R2-2-[Methyl(2-phenylethypamino]-8-nitro-4H-1, 3- benzothiazin-4-one, wherein R2 has the same meaning as defined in claim 1, F) 6-Trifluoromethyl -2-[methyl(2-phenylethypamino] -8-R1-4H-1,3 -benzothiazin-4-one, wherein R1 has the same meaning as defined in claim 1, G) 2-[4-(2-R14, 6-R15-Phenyl)piperazin-1 -yl ] -8 -nitro-6--(trifluoromethyl)-4H-1 3-benzothiazin-4-one, wherein R14 and R15 have the same meaning as defined in claim 1, H) 2-[Benzyl(R5)amino]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R5 has the same meaning as defined in claim 1, I) 2-[Benzyl(R5)amino]-8-nitro-6-R2-4H-1,3-benzothiazin4-one, wherein R2 and R5 have the same meaning as defined in claim 1, J) 2-[Benzyl(R5)amino]-8-nitro-6-chloro-4H-1,3-benzothiazin-4-one, wherein R5 has the same meaning as defined in claim 1, and K) 2-[Benzyl(R5)amino]-8-nitro-6-fluoro-4H-1,3-benzothiazin-4-one according to formula (I) of claim 1, wherein R5 has the same meaning as defined in claim 1.
A) 244-(2-R14, 5-R15-Phenyppiperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R14 represents H and R15 represents F, CI, or Br, B) 2-[4-(3 -R14, 5 -R15-Phenyl)piperazin-1 -yl ]-8-nitro-6-(trifluoromethyl)-4H-1 ,3 -benzothiazin-4-one, wherein R14 represents H and R15 represents F or CI, C) 2-[Benzyl(methyl)amino]-8-nitro-6-R2-4H-1, 3-benzothiazin-4-one, wherein R2 represents CF3, Cl or F, D) 2-[Benzyl(R5)amino]-8 -R1 -6-(trifluoromethyl)-4H-1,3- benzothiazin-4-one, wherein R1 represents CF3, NO2, NHOH or NR7R8 and R5, R7 and R8 have the same meaning as defined in claim 1, E) 6-R2-2-[Methyl(2-phenylethypamino]-8-nitro-4H-1, 3- benzothiazin-4-one, wherein R2 has the same meaning as defined in claim 1, F) 6-Trifluoromethyl -2-[methyl(2-phenylethypamino] -8-R1-4H-1,3 -benzothiazin-4-one, wherein R1 has the same meaning as defined in claim 1, G) 2-[4-(2-R14, 6-R15-Phenyl)piperazin-1 -yl ] -8 -nitro-6--(trifluoromethyl)-4H-1 3-benzothiazin-4-one, wherein R14 and R15 have the same meaning as defined in claim 1, H) 2-[Benzyl(R5)amino]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, wherein R5 has the same meaning as defined in claim 1, I) 2-[Benzyl(R5)amino]-8-nitro-6-R2-4H-1,3-benzothiazin4-one, wherein R2 and R5 have the same meaning as defined in claim 1, J) 2-[Benzyl(R5)amino]-8-nitro-6-chloro-4H-1,3-benzothiazin-4-one, wherein R5 has the same meaning as defined in claim 1, and K) 2-[Benzyl(R5)amino]-8-nitro-6-fluoro-4H-1,3-benzothiazin-4-one according to formula (I) of claim 1, wherein R5 has the same meaning as defined in claim 1.
3. A compound according to formula (I) of claim 1, selected from the group consisting of:
2- {Methyl [(1 R) - 1 -phenylethyDamino1-8-nitro-6-(trifluoromethyl)-4H-1 ,3-benzothiazin-4-one, 2-[4-(4-Chlorophenyl)piperazin-l-yl]-6,8-dinitro-4H-1,3-benzothiazin-4-one, 2-[4-(zyl(ethyl)one, and 2-[Benzyl(methyl)amino]-6-chloro-8-nitro-4H-1,3-benzothiazin-4-one, or a salt thereof.
2- {Methyl [(1 R) - 1 -phenylethyDamino1-8-nitro-6-(trifluoromethyl)-4H-1 ,3-benzothiazin-4-one, 2-[4-(4-Chlorophenyl)piperazin-l-yl]-6,8-dinitro-4H-1,3-benzothiazin-4-one, 2-[4-(zyl(ethyl)one, and 2-[Benzyl(methyl)amino]-6-chloro-8-nitro-4H-1,3-benzothiazin-4-one, or a salt thereof.
4. Use of a compound of formula (I) or a salt thereof as defined in any one of claims 1 to 3, for the preparation of a pharmaceutical composition.
5. Use of a compound of formula (I) or a salt thereof as defined in any one of claims 1 to 3, for the preparation of a medicament for the therapeutic or prophylactic treatment of microbial infection in mammals.
6. The use according to claim 5, wherein the microbial infection in mammals is a tuberculosis or leprosy infection.
7. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 and a pharmaceutically acceptable medium.
8. A compound as defined in any one of claims 1 to 3 or a salt thereof for use in a method for the therapeutic or prophylactic treatment of microbial infection in mammals.
9. A compound as defined in any one of claims 1 to 3 or a salt thereof for use in a method for the therapeutic or prophylactic treatment of tuberculosis or leprosy infection in mammals.
10. A method for the preparation of 2-NR5R6-4H-1,3-benzothiazin-4-ones as defined in claim 1, comprising reacting 2-chlorobenzcarboxamides with 1.1 to 2.5 times in excess of metal salts of alkylxanthogenate at a temperature of 20-100°C in a solvent and subsequently treating the resulting 2-alkoxy-4H-1,3-benzothiazin-4-one with an amine 1-INR5R6 in a solvent at a temperature of 20-100°C.
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| EP07013899A EP2020406A1 (en) | 2007-07-16 | 2007-07-16 | New antimicrobial compounds, their synthesis and their use for treatment of mammalian infection |
| PCT/EP2008/005142 WO2009010163A1 (en) | 2007-07-16 | 2008-06-25 | New antimicrobial compounds, their synthesis and their use for treatment of mammalian infections |
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| EP2380886A1 (en) | 2010-04-23 | 2011-10-26 | Vadim A. Makarov | Process for the preparation of 2-aminosubstituted 1,3-benzothiazine-4-ones |
| KR101851774B1 (en) * | 2010-11-19 | 2018-04-25 | 에꼴 뽈리떼끄닉 뻬데랄 드 로잔느 (으뻬에프엘) | 2-piperazin-1-yl-4h-1,3-benzothiazin-4-one derivatives and their use for the treatment of mammalian infections |
| EP2468746A1 (en) | 2010-12-23 | 2012-06-27 | The University of Queensland | Benzothiazinone compounds and their use as anti-tuberculosis agents |
| CN102276598B (en) * | 2011-05-27 | 2014-11-05 | 四川大学 | Benzothiazine-thione derivatives, preparation method thereof and purpose thereof |
| EP2570413A1 (en) | 2011-09-15 | 2013-03-20 | The University Of Queensland | Benzothiazinone derivatives as anti-tuberculosis agents |
| CN103508980B (en) * | 2012-06-14 | 2016-07-06 | 四川大学 | Benzothiazine-4-ketone derivatives and its production and use |
| US9708339B2 (en) * | 2014-06-09 | 2017-07-18 | University Of Notre Dame Du Lac | 1,3-benzothiazinone, sulfoxide, and sulfone compounds with electrophilic substituent |
| DE102014012546A1 (en) * | 2014-09-26 | 2016-03-31 | Martin-Luther-Universität Halle-Wittenberg | Antimycobacterially active substances, process for their preparation and their use |
| EP3072889A1 (en) * | 2015-03-23 | 2016-09-28 | Ecole Polytechnique Federale De Lausanne (Epfl) | 2-Homopiperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives and process for the preparation of 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides |
| RU2719736C2 (en) | 2015-07-27 | 2020-04-22 | 6С Вэйв Инновэйшнс Корп. | Granules of molecularly imprinted polymers for metal extraction and use thereof |
| CN105294597B (en) * | 2015-11-03 | 2017-11-24 | 华东师范大学 | Benzothiazine derivatives and its synthetic method and application |
| US11155542B2 (en) | 2016-09-22 | 2021-10-26 | University Of Notre Dame Du Lac | Antimicrobial compounds, their use for the treatment of mammalian infections and a new metabolic mechanism |
| RU2748350C2 (en) | 2016-11-03 | 2021-05-24 | 6С Вэйв Инновэйшнс Корп. | Molecularly imprinted polymer granules for extraction of lithium, mercury and scandium |
| CN108947952B (en) * | 2017-05-24 | 2021-09-21 | 中国医学科学院药物研究所 | 2-substituted amino-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compound and preparation method and application thereof |
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| CN111269197A (en) * | 2020-04-08 | 2020-06-12 | 苏州大学 | Benzothiazinone compound, preparation method thereof and application of compound as antituberculosis drug |
| CN111303075A (en) * | 2020-04-08 | 2020-06-19 | 苏州大学 | Benzothiazinone derivative, preparation method thereof and application of benzothiazinone derivative as antituberculosis drug |
| WO2022204902A1 (en) * | 2021-03-29 | 2022-10-06 | 苏州大学 | Benzothiazinone derivative substituted with trifluoromethyl at 6-position, and preparation method therefor and use thereof |
| WO2023065182A1 (en) * | 2021-10-20 | 2023-04-27 | 苏州大学 | Benzothiazinone derivative based on alkynyl linking arm, preparation method therefor, and use thereof |
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| US5690598A (en) * | 1996-09-27 | 1997-11-25 | Liang; Yung Jen | Wrist exerciser |
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| EP2020406A1 (en) | 2009-02-04 |
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| KR20100043071A (en) | 2010-04-27 |
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